Anti-Inflammatory Small Drug Adjunctive Therapy for Type 2 Diabetes

Type 2 diabetes (T2D) is characterized by concomitant insulin resistance and pancreatic beta
cell dysfunction. Disease prevalence continues to increase around the globe and is currently
estimated to be at more than 385 million affected people. As many as 1 in 3 people in the
United States could have diabetes by the year 2050 with significant economic consequences. In
2014, 1 in 5 health care dollars was spent to support the care of patients at a total
estimated cost > $245 billion. Overweight, insulin-resistant (IR) T2D individuals manifest a
chronic systemic inflammation which impairs beta cells and peripheral insulin sensitivity.
This systemic inflammation is associated with an atherogenic lipid profile and predisposes
individuals to higher risk for micro- and macro-vascular disease, irrespective of
well-controlled glycemia. Although a variety of pharmacologic approaches maintain daily
glycemic control, it is becoming evident that there is an urgent need to identify adjunctive
therapies to improve, insulin sensitivity, beta cell function, and HbA1c since they begin
deteriorating quite substantially by 5 years following initial treatment. Ideally, such
adjunctive therapies should be well-tolerated, easy to administer, should not promote
hypoglycemia and should also attenuate the systemic inflammation. The role of neutrophils in
T2D and metabolic inflammation represents an important gap in knowledge to better understand
inflammation in T2D especially since neutrophils are the most abundant leukocyte population
in humans and constitute the bulk of inflammatory leukocytes. Emerging evidence indicates
that neutrophils along with neutrophil-derived elastase serve as an important nexus of
T2D-associated inflammation. This trial offers a first-in-kind opportunity to better
understand the role of neutrophils in T2D diabetics. We hypothesise that inhibition of
neutrophil elastase (NE) will attenuate the chronic systemic background inflammation in
overweight and obese, IR T2D subjects and that the potential improvement in insulin
sensitivity and glucose control could concurrently facilitate functional maintenance and
induce the rescue of pancreatic beta cell mass.

To test the hypothesis, we propose a clinical trial that is comprised of the following two
aims:

Aim 1: To test whether orally-administered NEI adjunctive therapy in obese, IR T2D subjects
improves insulin sensitivity, glucoregulation and glycemic control. The primary endpoint is
the improvement of insulin sensitivity at 6 months compared to baseline, assessed by the
hyperinsulinemic-euglycemic clamp method. Secondary endpoints will include: i) Safety (rate
and severity of adverse events including hypoglycemia); ii) Glycemic and metabolic control
variables; iii) Assessment of functional beta cell mass (improvement in baseline oral glucose
tolerance test (OGTT) C-peptide levels and AUC, insulin secretion rate (ISR), body mass and
body fat-corrected insulin sensitivity; and iv) Changes in inflammatory variables.
Exploratory endpoints will include improvement of OGTT C-peptide (and C-peptide AUC)
trajectory, ISR trajectory, and decreased dose and dose frequency of background drugs.

Aim 2: To inform the changes in innate and cellular immunity conferred by the trial study
agents as a mechanistic approach to understanding the basis of potential efficacy. Evidence
of suppression of systemic inflammation will be examined during the trial. Changes in gene
expression of PBL and neutrophils may provide a signature of responder versus non-responder
status and/or of effect of therapy.

INCLUSION CRITERIA

1. Patients 21-75 years of age inclusive who meet the American Diabetes Association
standard criteria for type 2 diabetes mellitus (T2D).

2. Subjects are currently on metformin (at least 1000 mg per day) for a minimum period of
4 weeks prior to screening visit alone, or in combination with any of the following
diabetes medications or combinations:

1. DPPIV inhibitor (any dose level/frequency)

2. Sulfonylurea (any dose level/frequency)

3. GLP1 agonist (any dose level/frequency)

4. Sulfonylurea (any dose level/frequency) + GLP1 agonist (any dose level/frequency)

5. Meglitinide (any dose level/frequency)

6. SGLT2 inhibitor (any dose level/frequency)

3. Patients must have a body-to-mass index (BMI) of greater than or equal to 27 kg/m2.

4. Patients exhibit glycated HbA1c between 7.3-11.0 during eligibility screening and then
<=8.5 at final run-in visit.

5. Willingness to replace current diabetes therapies (listed in inclusion 2) with
metformin and saxagliptin and to adjust metformin dose during run-in period.

6. Subjects present adequate immune competence as assessed by immunoreactivity to viral
antigens (CEF Pool Assay) in vitro at the time of screening.

7. Participants of childbearing potential must agree to practice an effective form of
birth control which may include any one of the following: barrier method, oral
contraception, or surgery. These measures must be maintained throughout the study.

8. Subjects must have good peripheral venous access for the hyperinsulinemic-euglycemic
clamp and the 3-hr. OGTT procedures.

9. Patients understand the study procedures, alternative treatments available, risks
involved in the study, and voluntarily agree to participate by giving informed and
signed written consent for screening and enrollment.

10. Participants can be on anti-inflammatory therapies that are not diabetes-focused (e.g.
non-salicylate anti-inflammatory therapies, non-salicylate NSAIDs) and/or
anti-hypertensive medicaments or statins.

EXCLUSION CRITERIA

1. Patients with type 1 diabetes mellitus as defined by the American Diabetes Association
criteria or a history of ketoacidosis, or the patients are assessed by the study team
as possibly having type 1 diabetes mellitus confirmed with the presence of at least
one of the typical autoantibodies (insulin, GAD65, IA-2, ZnT8) AND a serum C-peptide
level of <0.7 ng/mL.

2. Patients have been treated with any therapies specific for their diabetes (other than
those listed in the inclusion criteria) within 4 weeks of the screening visit.

3. Patients have been treated with insulin within 2 months of the screening visit.

4. Patients are currently participating in or have participated in another study with an
investigational compound or device within the prior 12 weeks of signing the informed
consent or do not agree to refrain from participating in any other study while
participating in this study.

5. Patients have a history of hypersensitivity or any contraindication to DPPIV
inhibitors, including saxagliptin (Onglyza), or metformin based upon the labels of the
USA.

6. Patients are on a weight loss medication (such as orlistat, phentermine, Qsymia, or
Belviq) within the prior 6 weeks.

7. Patients are required by treating physicians to remain on any one of these agents
during the trial:

macrolide antibiotics, cisapride, anti-arrhythmics, steroids, rifampicin,
phenobarbital, phenytoin, secobarbital, carbamazepine, norethindrone, isoniazid.
AZD9668 is metabolized by CYP3A4, 3A5, and 2B6. SAXA is metabolized by CYP3A4 and 3A5,
potentially leading to drug-drug interactions with hypothetical adverse events in
patients on the above agents. Also, AZD9668 causes weak inhibition of CYP2C9 and
therefore patients on fluconazole, amiodarone, fenofibrate, fluvoxamine,
phenylbutazone, probenecid, sertraline, will also be excluded to avoid the
hypothetical adverse events due to this effect.

8. Patients have undergone major surgery within the 6 weeks prior to signing consent or
have any type or form of major surgery planned during the study (at the discretion of
the physician).

9. Patients are on or are likely to require treatment with 14 consecutive days or
repeated courses of pharmacologic doses of corticosteroids or any other
immunomodulatory agent. For example, patients requiring chronic systemic
corticosteroids (does not include topical or inhaled corticosteroids). Exceptions are
over the counter non-salicylate NSAIDs.

10. Enrollment or history of enrollment in a drug, or biologic therapy clinical trial that
affects the immune system within the past 12 months (e.g., systemic immunosuppressive
pharmacologics, immunosuppressive cytokines, therapeutic immunomodulating antibodies,
therapeutic immunomodulating fusion proteins and/or cytokine receptor decoys as well
as any intervention and/or non-intervention induced immunodeficiencies).

11. Prior history of coronary artery disease (defined as myocardial infarction, angina,
bypass surgery, or angioplasty)

12. Prior history of arrhythmia (excludes premature beats)

13. Prior history of heart failure defined as i) symptomatic OR ii) pulmonary edema, leg
edema or low ejection fraction (<40%)

14. Evidence of refractory chronic migraine (defined in ICHD-3 and Martelletti et al.).

15. History of persistent bradycardia within the last year prior screening visit (more
than three episodes in a calendar year of a heart rate <60 beats per minute that
required hospitalization on each of these occasions).

16. Leukopenia (<3000 leukocytes/microliter), neutropenia (1500 neutrophils/microliter),
lymphopenia (<800 lymphocytes/microliter), or thrombocytopenia (<125000
platelets/microliter),. any other clinically relevant abnormal hematology value.

17. Positivity for HIV, active CMV, chlamydia, any evidence of serious fungal infection,
active HSV1and/or HSV2 (determined as IgM positivity of 2 standard deviations higher
than the highest value of the test reference range), hepatitis B or C, at screening.
Minor skin fungus, or minor candidiasis is not an enrollment or treatment exclusion
criterion. Also, with the exception of HIV history, hepatitis B and C,
successfully-treated, disease-free individuals (> 6 months between time of successful
treatment confirmation and time at screening) would be eligible for enrollment in this
trial.

18. Patients are required by treating physician to remain on any medications listed in
inclusion #2 that directly affect glucose metabolism such as, but not limited to
thiazolidinediones, pramlintide, or amylin.

19. Vaccination with any form of live vaccine product within the last 3 months prior to
initiation of study agent administration.

20. Any chronic disease that in the opinion of the investigators would affect the
patient's safety and/or the integrity of the study outcome. This does not include
dyslipidemia, patients on statin or anti- hypertension treatment, or patients with
well-controlled hypo- or hyperthyroidism

21. Any other disease or disorder requiring chronic drug therapy except for treated
hypothyroidism (T4 and TSH should be within the normal reference range adjusted for
age), celiac disease, or statin- maintained, uncomplicated lipidemia.

22. Evidence of liver dysfunction, with ALT or AST> 1.5 times the upper limit of normal.

23. Evidence of renal insufficiency as indicated by blood creatinine of > 2 times the
upper limit of normal at baseline screening OR an eGFR < 45 mL/min. OR A past history
or current clinical evidence of renal failure or low creatinine clearance at
screening.

24. Females who are pregnant at the time of screening or unwilling to defer pregnancy
during the study period.

25. Lactating women.

26. Poor accessibility to veins for the 3-hour OGTT and hyperinsulinemic-euglycemic clamp
procedures.

27. The following therapies cannot be administered while patients are undergoing treatment
on this protocol: i) radiation therapy; ii) chemotherapy; iii) corticosteroids (except
for very short courses of topical or inhaled); iv) agents used to treat attention
deficit and hyperactivity disorder (ADHD); v) rifampicin or phenytoin; vi) other
protein, particle or cell vaccine immunomodulation therapies. If these therapies are
essential for treatment of other conditions, participation in this study will be
terminated.

28. A condition which interferes with the ability to accurately determine glycated HbA1c.
Examples include: Genetic variants (e.g. HbS trait, HbC trait), elevated fetal
hemoglobin (HbF) and chemically modified derivatives of hemoglobin (e.g. carbamylated
Hb in patients with renal failure); Any condition that shortens erythrocyte survival
or decreases mean erythrocyte age (e.g., recovery from acute blood loss, hemolytic
anemia); Iron deficiency anemia, iron replacement therapy

29. Subjects who cannot tolerate at least 1000 mg daily of immediate or extended release
metformin by the time of final run-in will be excluded from further participation.

30. Subjects who do not exhibit a glycated HbA1c level <=8.5 by the end of the run-in
period.